In a meeting between Scripps Research Institute Florida and the Civic Association this week, a topic of high interest to Palm Beachers was discussed about the ongoing efforts by Scripps to combat the Zika Virus.

Scripps Florida is a Civic Association Corporate Partner. The following report was presented:

Ongoing efforts by the Scripps Research Institute to combat the Zika Virus, and our priorities going forward

The following describes how The Scripps Research Institute might best apply resources to protecting mothers and infants from the worst health consequences of the Zika virus.

Background

The Scripps Research Institute has been pursuing four goals in its anti-Zika virus effort. These are:

- Development and improvement of a safe, effective Zika vaccine: improving the safety of the first likely vaccine to be tested in humans, and developing alternatives should this first effort falter.- Development of orally available small compounds that can be used prophylactically and in the early stages of an infection.- Development of injectable antibodies and biologics whose safety profile would make them useable in pregnant and soon-to-be-pregnant women.- A deeper understanding of Zika pathogenesis, with focus on mother-to-infant transmission at the placental barrier, the reasons for efficient neural infection, and the causes of Zika-induced microcephaly.

We have made significant progress in each of these four areas:

Vaccines.A prototype of a Scripps live-attenuated Zika vaccine have been developed and characterized at small scale. The Scripps vaccine has two important properties different from competing vaccine efforts. It is designed so that it cannot traverse the placental barrier, increasing its ability to be used in women whose pregnancy state is unknown. It is also modified to lower the chance, in rare cases, of worsening Zika infection or infection by other flavivirus infections, a continuing concern with all flavivirus vaccines. In the best case, our vaccine effort will take at least two years to reach the clinic, and several more to achieve widespread use.

Small antiviral compounds.We have initiated our first screen with a Zika virus replicon system using a pilot 4000-compound library. This first library is FDA approved so potent leads from this screen could be rapidly tested in humans. This screen proved that we can perform a high-throughput screen for anti-Zika compounds, but did not produce any silver bullets. We will therefore be undertaking a much larger screen of 400,000 compounds. The best leads from that screen will be modified through medicinal chemistry to minimize potential side effects and improve pharmacokinetics.

Antibodies.The developing of anti-Zika virus antibodies is our absolute highest priority because antibodies have exceptional safety profiles, and would be the only medical intervention justifiable in pregnant women in the next several years. Such an antibody can be used to protect – as a vaccine would – pregnant women who are uninfected, and protect the fetus of those who may be infected. It could also protect men and women living near a localized outbreak, and it could be used more widely to treat infected individuals. Scripps and other institutions around the country have identified a number of lead antibodies, but these antibodies need to be modified in well understood ways so that they do not make other viral infections worse, they need to be produced in quantities necessary for preclinical studies, they need to be compared in an unbiased manner in non-human primate models for their bioavailability and their efficacy against the Zika virus, and the best of these need to be tested for safety and efficacy in human clinical trials.

Pathogenesis.Scripps has developed and will soon publish on two very important insights in the pathology of Zika virus disease. First, in a very productive collaboration between our neuroscience and our immunology departments, we have defined the mechanisms by which the virus destroys the neurons of neonatal mice. Second, in some of the best basic science work at the Institute, we have defined the molecular basis for how the Zika virus, but not other closely related flaviviruses, crosses the placental barrier to access the fetal bloodstream. Both of these studies provide key insight into the development of vaccines and antiviral compounds.

Recommendation

While all our priorities are critical, the effort that will have the largest immediate impact on health outcomes in the United States is the development of a safe, potent, and bioavailable antibody. Again, antibodies have exceptional safety profiles, and would be the only medical intervention justifiable in pregnant women in the next several years. There are currently at least eight described antibodies for Scripps and several other institutions across the counter that should be included in a test panel, with several more on the way. These antibodies, as well as combinations of the best performers, should be down-selected in an unbiased manner to four by comparing their biophysical properties and their anti-Zika activities in the laboratory. These four should then be compared for half-life and anti-Zika activity in non-human primate models as quickly as feasible, and combinations of the top performers should be similarly evaluated. To do so, they need to be engineered so that they cannot worsen dengue and Zika infections using a well-established approach, they need to be produced at sufficient scales for pre-clinical use, and they need to be tested for safety and efficacy in non-human primate studies.

Unfortunately non-human primate studies are both necessary and expensive. An accelerated laboratory effort as described would cost approximately $200,000, and a correctly run non-human primate study comparing four best performing antibodies with appropriate controls will cost approximately $350,000. Note that these studies do not result in death or long-term harm to the animals. We are actively raising money for this effort in sincere hopes that it will prevent many cases of microcephaly in a very short time frame.